Obesity greatly increases the risk of atherosclerosis, the leading cause of cardiovascular disease (CVD) and death in obese patients. Because of the obesity epidemic, CVD associated with obesity is a rapidly growing problem. The mechanisms whereby obesity worsens atherogenesis are still largely unknown, but adipose tissue inflammation has been implicated in obesity-accelerated CVD. The arterial smooth muscle cell (SMC) plays a critical role in atherogenesis. This project will investigate the role of the glucose transporter GLUT1 in SMCs by using new mouse models in which GLUT1 (Slc2a1) is overexpressed or knocked-down in SMCs. The overall hypothesis, based on preliminary data, is that SMC-GLUT1 is of critical importance for the obesity- induced arterial metabolic signature and the SMC inflammatory phenotype, and subsequently the obesity- accelerated atherosclerosis. The first specific aim is to ask the question: Is SMC-GLUT1 required for the arterial metabolic signature of obesity and for obesity-accelerated monocyte recruitment and atherosclerosis? Careful studies on lesions in obese mice with SMC-targeted GLUT1 overexpression and inducible SMC-targeted GLUT1-deficiency, and evaluation of monocyte recruitment will be completed. Targeted metabolomics studies will reveal whether SMC-GLUT1 is required for the metabolic abnormalities that characterize the aorta in obese mice. The second specific aim will ask the question: Does SMC-GLUT1 exert its pro-atherosclerotic effects in obesity through a pathway that involves branched-chain amino acids, inflamed adipose tissue and/or the myeloid chemokine receptor CXCR2? It is hypothesized that SMC-GLUT1 promotes atherosclerosis through a pathway that requires altered arterial metabolism (increased glucose flux and branched-chain amino acids), inflamed adipose tissue, and/or the myeloid cell chemokine receptor CXCR2. Investigation of the mechanisms involved, using branched-chain amino acid dietary supplementation, fat transplant studies, bone marrow transplant studies using donor mice with myeloid cell-targeted CXCR2-deficieny, flow cytometry and ex vivo studies will be performed. Regulation and effects of endogenous GLUT1 in human and mouse SMCs will also be studied. The proposed studies are designed to investigate a novel link between obesity/adipose tissue inflammation and atherosclerosis. The studies will shed light onto the mechanism of the increased atherosclerosis associated with obesity. The project therefore has the potential to identify new prevention and treatment strategies for CVD associated with obesity.